Table of contents
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`1.
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`Historical review . .
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`2.
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`2.2
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`Product description .
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`Description of the finished medicinal product .
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`Chemical name and structural formula of the active ingredient .
`Presentation .
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`2.4
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`2.5
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`Indications .
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`2.6
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`2.7
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`Type of use . .
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`Dosage by individual and daily doses .
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`3.
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`3.1
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`Toxicology .
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`Acute toxicity .
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`3.2
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`Subchronic toxicity .
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`3.3 Mutagenic and carcinogenic effects .
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`3.4
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`Reproductive toxicity and teratogenic activity .
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`4
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`Pharmacology .
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`4.1
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`Efficacy in animal models and cell culture .
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`r 4.2 Mechanism ofaction . . .
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`5.
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`Pharmacokinetics .
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`5.1
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`Site of absorption and absorption kinetics . . .
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`Protein binding .
`5.2
`5.3 Concentration in tissue .
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`5.4
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`5.5
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`5.6
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`5.7
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`CSF penetration .
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`Biological half~|ife .
`Elimination .
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`FRESENIUS KABI 1007-0002
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`FRESENIUS KABI 1007-0003
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`5.9
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`Elimination in impaired renal function .
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`5.10 Elimination in impaired hepatic function .
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`5.11 Dialysability .
`5.12 Metabolism .
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`6.1
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`Clinical efficacy .
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`Hodgkin's disease (stage II-IV)
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`6.2
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`6.3
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`Non-Hodgkin lymphoma (NHL)
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`6.4
`6.5
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`Plasmocytoma (multiple myeloma I MM)
`Breast cancer .
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`6.6
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`In clinical evaluation — lung cancer .
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`6.7
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`6.9
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`In clinical evaluation — gastrointestinal tumours .
`In clinical evaluation — head and neck cancer .
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`?.1
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`Tolerability .
`General .
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`?.2 Hematopoietic system .
`7.3 Gastrointestinal tract .
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`Nervous system .
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`. 44
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`7.5 Allergic reactions! hypersensitivity .
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`?.6
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`Cardiovascular system .
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`. .45
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`7.?
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`Skin, mucosa .
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`. 45
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`7.8
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`Local irritations .
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`?.9 Other side effects .
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`. 45
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`"M 0 Note for drivers .
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`. 46
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`8.
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`overdosage .
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`8.1 Main symptoms and general signs of overdosage .
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`. 46
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`. 4?
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`8.2
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`Treatment of overdosage and intoxication .
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`9.
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`Summary .
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`. 43
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`. 49
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`10.
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`References .
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`. 55
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`11. Abbreviations .
`
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`Directions for Use for Physicians .
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`. .56
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`FRESENIUS KABI 1007-0004
`
`

`
`FRESENIUS KABI 1007-0005
`
`

`
`Historical review
`
`Bendaniustine (LMET 3393) was developed in the early 1960s by
`
`Ozcgowski and co—workers (44) at the Institute of Microbiological
`
`and Experimental Therapy in Jena (Ge.rmany).The aim of the synthesis
`
`was to combine a purine and amino acid antagonist with an alkylating
`
`nitrogen mustard group (bifunctional allcylating agent). A major
`
`advantage of the newly developed compound compared to chlora1nbu—
`
`cil, for example, was its water solubility (45).A3-iger et al- ('3) published
`
`initial results of the successful clinical use ofbendaimistine in plasn2o—
`
`cyton-La patients- Bendarnustine was marketed {tom 1971 to 1992
`
`under the trade name Cytostasmi“ by thejenapharrn company. Since
`
`1993 the cytostatic is being marketed by ribosephartn Grnbl-I under
`the name Rjbomilstin’.
`
`FRESENIUS KABI 1007-0006
`
`

`
`
`
` Product description
`
`2.1 Description of the finished medicinal product
`Ribomustinm
`
`Active ingredient: bendarnustinehyd.roci1.loride
`
`2.2 Chemical name and structural formula of
`
`the active ingredient
`(5—'[bis(2—chIoroethyl)—21t11ino]—1—mcthyl-L’—|3enzimjdazolc) butyric acid hydro-
`
`chloride (Figure: 1).
`
`Structural formula
`
`Cl-CH;-CH2-..\ N
`cI-cH.—cH,/
`
`N
`
`N
`
`>—(CHJ.-COOH-HCI
`
`Figure 1: Structural formula of bendarnustinahydrochlorida
`
`CH,
`
`Empirical formula
`
`C,.,H,,,Cl,N3O;-HC1
`
`Molecular weight
`
`394.7 {calculated with reference to the anhydrous substance)
`
`2.3 Presentation
`
`One vial with pierceable stopper with 5:": mg of the dried substance contains
`
`25 mg of bctidamustitichydrochloride.
`
`One vial with pie.-rceable stopper with 220 mg of the dried substance contains
`
`100 mg ofbendamustinchydrochioridc.
`
`FRESENIUS KABl 1007-0007
`
`

`
`2.4
`
`Indications
`
`Rihomustin“ is indicated as single—agent therapy or in combination with other
`
`antineoplastie drugs For the treatment oiithe following malignancies:
`
`- Hodgkin's disease (stages II—lV)
`
`' non-I iodgkiifs lvlnphoma
`
`- plasllaocytoma
`
`' chronic lymphocytic leukemia
`- breast cancer.
`
`2.5
`
`Contraindications
`
`Rihon1ustin'” should not he used in the following cases:
`
`° known hypersensitivity to bendalnustine and/or Inaunitol
`
`0 pl'Cg'I]a.I‘JC}C presumed pregnancy and during breast Feeding
`
`0 iinpairnient ofrenal function (glomertilar filtration rate < 30 1111/minute)
`
`' severe liver parenchvmal damage
`
`° jaundice
`
`0 existing severe bone marrow depression and severe blood count abriornialilies
`
`° major surgery less than 30 days before starting therapy
`
`- infcctioi1s.espeeial1y associated with leukopenia (risk of generalization oFinfection)_
`
`2.6
`
`Type of use
`Riho1nustin‘“ is administered as a short intravenous inftlsion over 30 to 60 minutes
`
`afier reconstitution in aecordance with the instructions.
`
`The ready—to—use solution is prepared as follows:
`
`Dissolve the contents oF one Rihon'1ustin" vial with piereeable stopper containing
`
`35 ]‘lflgbi.i11L‘l;.I.IT1i.lSi:i11t" in 10 ml by shaking.
`
`Dissolve the contents of‘ one R.iho:n11stin"" vial with pierceable stopper containing
`
`100 nag hendamustine in 40 nil by shaking.
`
`As soon as a clear solution is obtained (this usually takes 5 to 10 minutes). dilute the rota]
`
`dose of Rihomustin" innnediately with 0.9 00 NaCl solution to produce a final volume of
`about 500 ml.
`
`IO
`
`FRESENIUS KABI 1007-0008
`
`

`
`2.7 Dosage by individual and daily doses
`Benclziilmstiile is administered as rnonotlierapy or in combination with other chemothera-
`
`peutic agents in :1 variety of dosages and i‘egi1ne1is.'I‘liere is no “standani dosage” and no
`
`“standard regimen”. Some widely used dosages and regimens which have been evaluated
`
`in clinical studies are given below. For Further dosages and regimens please refer to the
`
`medical literature; illibriiiatiozi is also available on request.
`
`Treatment should be terminated if the leukocyte and/or platelet count has decreased to
`
`levels 5 3,000/pl and 5 75,000/p,l respectively.
`
`Ribo1nustin"" treatinent can be continued after the leukocyte count has increased to 2.
`
`‘l-,i}0il/|.1.l and the platelet count to 2 l00,l'l00/ttl.
`
`'l"l1e portion of Free bcndarnustine liydrocliloricle may be increased by up to 30% if the level
`
`ofalbuniin in plasma is very low (5 30 g/l).1"-S dose reduction may tlierefore be consiclered
`
`in such cases. Examples of different dosages and regimens (depending on the inclication):
`
`HtIiigleir'iI< iiisrerise {.s‘i't'{g£’5 II—IL-T)
`
`“DB3gBg rggir_nen";
`
`daunorubicin
`
`25 mg/tn”
`
`on days 1-i-15
`
`bleornycin
`
`Virlcristine
`
`I0 mg/nr"
`
`on days 1+ 15
`
`1.4 nlg/111"
`
`on days l+l5
`
`Ribon1ustin""
`
`50 nig/In”
`
`on days I— 5
`
`repetition oftlie cycle aFte1' 4 weeks.
`
`Nflfi-Hfltigkiiii lyi-iiplimiiri
`
`“BOP regri1r1en":
`
`Ribornu5ti11""
`
`60 mg/m’
`
`on days 1-5
`
`vincristine
`
`2 ing/n1"
`
`on day l
`
`prednisone
`
`100 mg/n1"
`
`on days l~5
`
`repetition oftlie cycle afier 3 weeks.
`
`l’lrisrimrytorm:
`
`“BP regimen":
`
`Ribornusti11""
`
`120-150 rng/n1" on days 1+2
`
`prednisone
`
`60 nig/111“
`
`on days 1+4
`
`repetition ofitlie cycle after 4 weeks’.
`
`Ciiim-tit ll}1f1ipi'!t?(}’Ii( leuieetrifrr
`
`Ril'iomusti11""
`
`80— l 00 mg/ 111-’
`
`on days 1+2
`
`repetition of the cycle after 4 weeks.
`
`Breast ramrr
`
`“BMF regimen":
`
`Ribou1ustin""
`
`I20 mg/in-‘
`
`on days 1+8
`
`lnetliotrexate
`
`40 mg/n1-'
`
`on days 1+8
`
`5—tluorouaci.l
`
`600 mg/n1"
`
`on days 1+8
`
`repetition of the cycle after 4 weeks.
`
`“Second line therapv”:
`
`Ribor11ustin“"
`
`100-150 nrg/I113 on days I-I-2
`
`repetition of the cycle after 4 weeks.
`
`Note:
`
`No dose recoirnnenclations can currently be given for children, since there is no experience
`
`with this age group.
`
`111
`
`FRESENIUS KABI 1007-0009
`
`

`
`Toxicology
`
`3.1 Acute toxicity
`The LDW in mice aficr intravenous and intraperitoneal administration is
`
`80 mg/kg body weigl'1t.’I‘he 1.135,. in rats after intravenous adrninistration
`
`is 40 nag/kgbody weight (62).
`
`3.2 Subchronic toxicity
`Bendamustine hydrochloride was administered orally to rats in dosages of 10,
`
`'20, 40, 80 and 160 mg/kg daily over a period of28 darys.Tl:ie substance was
`
`not lethal up to a dose of 40 mg/kg. Hematologic and non-hematologic side
`
`effects were slight to moderate and reversible after treatment terrnination.Tl1e
`
`LD,,, was reached at dosages of 2 80 mg/kg daily.
`
`In dosages of 80 and 160 mg/kg benclannistine induced bone marrow aplasia,
`
`atrophy oflymphatic tissue and liistopathologic abnormalities of the kidneys
`
`and intestine.'I'here was no evidence of damage to other organs (33).
`
`Subchronic toxicity studies in dogs were performed with a 30-minute daily
`
`intravenous infusion administered in three 4-day cycles. Each of the Cycles was
`
`followed by a 31-day recovery phase.The Following side effects were observed
`
`at doses of 6.6 mg/kg/day: vomiting, salivation, weight loss and loss of appe-
`
`tite. During the recovery phase evacuation ofliquid stool and behavioural
`
`changes were observed. Gross examination revealed rnucosal liyperernja and
`
`intestinal hemorrhagic zones in these animals. Microscopic analysis also revea-
`
`led pronounced changes to lymphatic tissue as an indicator ofimmnno-
`
`suppression, and changes to kidneys, testes and prostate. Doses of 3.3 and
`
`1.65 mg/kg/day, however, were tolerated with only minor toxicity (slightly
`
`reduced food consumption, slight weight loss, dose-dependent leukocyte
`
`suppression) (I1).
`
`11
`
`FRESENIUS KABI 1007-0010
`
`

`
`3.3
`
`Mutagenic and carcinogenic effects
`Bcndalmistinc induces chromosome aberrations and exhibits mutagcnic activity in cell
`
`culture: and anim:11 models (22: 54; 55).
`
`Lung tumours and mammary carcinomas were detected in mice after administration of
`
`bendamL15tinc ([5).
`
`3.4
`
`Reproductive toxicity and teratogenic activity
`Bcrndamustinc was cmbryotoxic and temtogcnic in pregnant mice (24).
`
`12
`
`FRESENIUS KABI 1007-0011
`
`

`
`Pharmacology
`
`4.1 Efficacy in animal models and cell culture
`Schnabel et a1. (62) demonstrated with three experimental murine tumours
`
`(leukenlia I.A_]l , sarcoma l80,Ehrlicl1 ascites carcinoma) that bendamustine is
`
`comparable to cyclophosphamide in its suppressive efllect on tumour growth-
`
`FuIther studies (14) have evaluated the antineoplastic activity of bendamustine
`
`in 8 experimental murine tumour models using different transplantation tech-
`
`niques and forms of administration. Bendamustine exhibited a suppressive
`
`effect on tumour growth for 6 ttnnours (Ehrlich ascites ca:rcinoma,1euken:u'a
`
`L1210, leukemia P3 88, rnelanonta B16, Lewis lung carcinoma and lymphoma
`
`ABDt6) (4).
`
`Strurnberg et al. (66) studied the cytotoxic effect ofbendarnustine on lzlumarl
`
`ovarian and n1-anmtary carcinoma cell lines (including cisplatin and doxorubi-
`
`cin resistant cell lines). Besides the cytotoxic activity the investigators also
`
`demonstrated incolnplete cross-resistance with other alkylating agents (Cvclo—
`
`phosphanljde, rnelphalan and carmustine).
`
`Schwaenen et al- (65) studied the in vitro induction of apoptosis in B-CL],
`
`cell lines by bendarnustine and fludambine alone and in combination- Benda-
`
`mustinc showed dose—1-elated apoptosis induction of 8% to 94% after 48 hours.
`
`13
`
`FRESENIUS KABl 1007-0012
`
`

`
`In 10 of 12 B—CLT_. cell lines the combination of bendaniustine and fludarabine resulted
`
`in a synergistic effect after 48 hours, i.e. a 14-fold higher apoptosis rate than expected
`
`(see Figure 2).
`I00‘-—
`
`- fludarabine EL? ixgfml
`I bendarnimlne 2 pgfml
`9 expected
`I combination
`
`95,99
`fgsalfl
`‘I
`
`
`
`
`an :
`
`E to —
`
`40 -—-
`
`% E §
`
`an —
`
`0
`
`2-! I1
`
`I15 1'!
`time
`
`?2 h
`
`Figure 2: En haneed apoptosis of B—CLL lymphocytes on incubation with bendarnustine 2‘ fludarablne (accor~
`cling to Schwaenen et aI.)
`
`Chow et :11. ('12) studied the in vinti induction ofapoptosis and inhibition of proliferation of
`
`neoplastic cells in low—grade I"~UiL using combinations of established cytotoxic drugs with
`bendarnustine.Tl1e coinbination ofbenda1nL1stine with elaclribine resulted in additive or
`
`even synergistic effects on -apoptosis and inhibition of cell proliferation on all tested cell
`
`populations (DOI'Il'1—2;WSU—NI-‘iI.; ex vivo cells ofpatients with C[.I.,le11kemic low—
`
`grade B—NI‘lI.,T-NI-lI.). In contrast, the combination ofbendalnnstine with either doxoru-
`
`bicin or mitoxantrone showed antagonistic effects both on apoptosis and inliibition of cell
`
`proliferation (Figure 3).
`
`Combination index of tested drug combinations
`
`15 —
`
`5 0 —
`
`CI
`
`
`
`Antagonism
`Ci:-v'i
`
`synergism
`Cici
`
`
`
`14!
`
`B1-D
`
`E+M
`
`B-i-C
`
`Figure 3: Combination index {CI} for apoptosis {A} and inhibition of pml1ferat1tm{P1_
`Drug combinations;
`B+ B: bendarnustme + doxorubiclun.
`3+ M: ben da mustine + mitoxan Krone.
`8+ C. ben darn ustine + cladribine
`
`FRESENIUS KABI 1007-0013
`
`

`
`Bendamustine induced apoptosis was p53 izidependent, thus the apoptosis cascade seems
`
`not to be influenced by benclaniustine.Therefore, the expression patterns ofthe drug coni-
`
`binacions containing bendamustine depended on the expression caused by the combination
`
`partner (cloatorubicin. niitoxantrone or eladribine).
`
`This cell nioclel demonstrated that liendaanustine has a different n1echa_nisn1 of interaction
`
`than that ofpnrine analogs and a different manner of induction of apoptosis than alcylating
`
`agents.
`
`These results suggest that schedules using combinations ofbendamustine and :111tI1racy—
`
`clines should not be recoinlneiided for the treatment oflow~grade N] 11., whereas benda-
`
`niustine combined with cladribine could be considered for the development of future
`
`l'I't"2ll‘l'1'lL’Dt St1'3[E‘gi{‘5.
`
`5-ichleucher et al. (61) studied the interaction of bendatnusrine with vinorelbine, 5—FU and
`
`paclitaxel in cytotoxicity assays. In addition, he studied whether the efficiency is influenced
`
`by the sequence ofthe drugs.
`
`Bendatnnstine showed significant cytotoxicity in hL1n1a.n tumour cell lines. even in those
`
`with MDR-1 activity. The sequence ofhendamilstine and 5-FU showed additive to syner-
`
`gistic interactions. Bendainitstine and vinorelbine showed a sequence depentient synergism
`
`in 2 different cell 1ines.Tlie cytotoxic activity ofpaclit;Ls:eI may be increased in combinati-
`on with bendaniustine.
`
`Interactions of the cytotoxic agents bendamustine. 5-FU, paclitaxel, and vinorelbine
`
`on breast cancer cell lines MCF-7 (wild type) and MDA-MB231°
`
`hendainustine before 5—FU
`5—FU before bendalmistine
`
`MDA—MB23l
`
`bendainustine before :3—FU
`
`5~1"-U before liend-alnustine
`
`MCI"—7
`
`bendaniustilie before paclitaxel
`
`paclitaacel before bendaniustine
`
` MCIF—7
`
`MB23l
`
`bendaniustine before pacljtagtel
`
`paclitaxel before be11dan1i.1sti1ie
`
`MCI‘—7
`
`bendannistine before vinorelbine
`
`vinorelbine before bendamustine
`
`MDA-M13231
`
`bendamustine before vinorelbine
`
`vinorelbine before bendarnustine
`
`synergistic
`aelditive
`
`synergistic
`
`antagonistic
`
`synergistic
`
`antagonistic
`
`antagonistic
`
`synergistic
`
`synergistic
`
`synergistic
`
`synergistic
`
`synergistic
`
`“ lncubations with bendamustine, paclltaxel, and vinorelbine for 2 h, with 5—FU for 24 h
`
`15
`
`FRESENIUS KABI 1007-0014
`
`

`
`4.2 Mechanism of action
`
`Bendamustinc is a bifunctional alkylating agent with antineoplastic and cytociclal properties
`
`(Figure 4).
`
`benzimiclazolc ring:
`
`purine analogue N——n]u§ta_fd—gr[)up;
`
`
`alkaneearboxylic acid:
`alkylating agent
`provides water-solubility
`
`(reduced toxicity due
`
` to electron affinity)
`
`Figure 4: Chemical-functional structure of bendamustine
`
`The efficacy is attributable mainly to crosslinking of the DNA single and double strands by
`
`a.lky1ation.This produces a disturbance of the matrix fimction of DNA and DNA synthesis.
`
`There is also crosslinkjng between DNA and proteins and between proteins tl1Cl‘I‘LiClV6S.
`
`It is not yet known whether the benzimidazole ring possesses additional antimetabolite pro—
`
`perties (18; 30; 66; 68).
`
`FRESENIUS KABI 1007-0015
`
`

`
` Pharmacokinetics
`
`5.1 Site of absorption and absorption kinetics
`Not applicable since intravenous administration.
`
`5.2 Protein binding
`The substance is bound to plasma proteins (preferentially albumin) to the
`
`extent of 95% (16;41;42).The protein binding behaviour of bendainustine
`
`has been shown to be unaffected by low plasma albumin levels, age over
`
`70 years and advanced tumour stages (15).
`
`5.3 Concentration in tissue
`
`No cumulation is to be expected (42; 47).
`
`5.4 CSF penetration
`No information is available regarding CSF penetration.
`
`5.5 Placental transfer
`
`No information is available regarding placental transfer.
`
`5.6 Excretion in breast milk
`
`No information is available regarding excretion in breast milk.
`
`FRESENIUS KABI 1007-0016
`
`

`
`5.7
`
`Biological half-—life
`Following i. v. bolus injection of bendarnustine in the usual therapeutic closages,tl1e plasma
`
`level in man follows a biphasie exponential pattern.'l“ne elimination iiaifllife two: is bet-
`
`ween 6 and ll) n1inutes,:n1d the terininal elimination hall"-life t,,3B between 38 and 36
`
`minutes. After i. V.1it'lJ1'lil1iStI'atiOI1 in several studies the central volume of distribution was
`
`between 8.6 and ll.2 l. Under steady state conelitioils the volume of distribution was
`
`15.8 * 30.51(4l;42).
`
`I 5.3
`
`Elimination
`
`Elimination is rapid, bipliasie and preelominantly renal. Mean total clearance was calculated
`
`as 59.8.‘) - 826.2 ml/minuteflilie Following Fractions, referred to the total amount of admi-
`
`nistered parent compound, were detected in urine: bendarnustine 45.3%.l1ydroxy~benda—
`
`I11l.lSl.'lJ1E' 33.8%, an unidentifiecl polar metabolite 13.4%, Li—liyt‘lroxy—bendanmstine 8%, an
`
`unidentified apolar metabolite S.l°u and N-demethy|—bendarnustine l.5%. Mainly polar
`
`metabolites are eliminated by the biliary route (41; 43).
`
`5.9
`
`Elimination in impaired renal function
`Benelamiistine is predominantly eliminated by the renal route.Tl1e drug should
`
`not be given to patients with impaired renal function (glotuertdar filtiatioli rate
`
`< 30 nil/minute).
`
`5.10
`
`Elimination in impaired hepatic function
`Beiidamtlstine is Inetabolized in the liver and eliminated to a small extent (nlainly polar
`
`metaiiolites) via the biliary sy5tetn.The drug should not be given to patients with severe
`
`hepatic pareneliynial damage and jaundice.
`
`5.11
`
`Dialysability
`It is 11ot yet known whether benda1nu.s‘tine or its metabolites are Liiil.l}*‘Z3lJlt".
`
`13
`
`FRESENIUS KABI 1007-0017
`
`

`
`5.12 Metabolism
`
`Btrndamustinc is metaboliztrd mainly in the 1ivc:r.'1'hc main biotrsmsformation product is a
`
`cytotoxic hydroxy derivative (I5—hydroxybc'ndamustin c), which is Formed by hydroicylation
`of the b11t:111oic acid side cl1ain.This substance shows elimiilation kinetics Si11'1fl3t to those
`
`ofthr: pzlrcnr compound (tug about 19 mim1t::s), In the dose range 0.5-5.0 mg/kg, clearan-
`
`cc and the AUC (B-01 I—b::ndamu5ti11c) /'AUC (bendzlmtlstine) ratio are nomdost: depen-
`
`dent. Further ide11tified mu-taholites are 1110lmhydrorcybendamustinre, dfl1yd1'oxybend:L1nu5I:i—
`
`ms, hydroxy—B—hydroxybcnclam115tinC and N—demcthylbcndamllstine (41; 43; 48) (Figurc 5).
`
`C|CH,CH,,\
`
`>—CH,CH.»CH:COUH
`
`HDCH.CH,.\
`
`ClCH.CH,/N N
`T
`CH.
`OH-henrlamustine
`
`§-—CH,CH,CH,COOH
`
`'""'*am"5""P
`
`T/ cm \
`
`
`
`{',|l'.H.EH.-.,\N
`CIcH,cH,/
`
`N
`
`%CH;CHyCH;CO0H
`
`TH
`N-demelhjrlhendanlusllne
`
`
`
`{T}
`pol rmmholrt
`pn|:v nietabolrt: {ll}
`apolal melahoilhe HIT)
`
`0HCHaCHa-..__
`uHcH,cu,/"
`
`N
`
`>—CH,CH,-{HIUOH
`
`T
`I
`E“
`di-OI!-heudalnustirle
`
`ClCH.CH,\
`
`cIcH.t:H,/N
`
`>—EH.CHOHCH.COC|H
`
`N
`T
`CH;
`B~0H~|n-ndarnustlne
`
`HOCH.CHn.,\
`cIcH,cH,/ N
`
`N
`
`>—l'_HyCHOHCH¢CO0H
`
`T
`,
`C"
`r_IHvfi-OH—he|u.Iamustinu
`
`Figure 5: Metabolism of bendamustine (act. to Preiss et all.)
`
`19
`
`FRESENIUS KABI 1007-0018
`
`

`
`Clinical efficacy
`
`6.1 Hodgkin's disease (stage ||~|V)
`Initial research findings have shown that bendamustine is at least as effective as cyclo-
`
`plrosphamide (3).
`
`In 3 Further prospective randornized study; I-Itiche et co-workers (31) compared various
`
`chernotherapy protocols in 73 evaluable patients with I—Iodgldn’s disease stage IIIB or
`
`IV (Ann Arbor c1assifical:iou).O11ly patients with primary or secondary resistance to the
`
`CVPP regimen (cyclophosphamide / vinblastine / procarbazine / predriisone} were
`
`enrolled in the study. One treatrnent Cycle iastecl 28 days, and day 16 to day 28 were
`treatment-fi-ee.
`
`Treatment regimens
`DBVB (n = 38)
`D-aunorubicin
` 25 mg/mi i.v. on days 1 + 15
` Bleomycin
`10 mg/m-’ i.v. on days 1 + 15
`
`Vincristine 1.4 mg/m’ i.v. on days 1 + 15
`Bendamustine
`50 mg iv. on days 1 — S
`
`
`
`
`
`25 mg/In‘ i.v. on days 1 + 15
`
`10 mg/m3 i.v. on days 1 + 15
`
`1.4 mg/nf‘ i.v. on days 1 + 15
`
`150 mg/m'*' i.v. on days 1 — 5
`
`ABVD (n = 35)
`
`Doxorubicin
`
`Bleornycin
`
`Vincristine
`
`Dacarbazine
`
`
`
`Study results.
`
`
`
`Number of
`Median
`
`remission
`patients
`
`duration
`(months)
`
`Median
`survival
`
`(months)
`
`
`
`
`
`20
`
`FRESENIUS KABl 1007-0019
`
`

`
`Co11elusio11s:The eoinbination tlierapy eciiitainiiig l.'!CI'1Ll€L1"I1I_'lSti.1'1E
`
`is equiv:1lent in effective-
`
`ness to the reference therapy but is better tolerated.
`
`Herold et al. (35) evziltiateel the efficacy ofcyclie alternating eliernothenipy in the therapy
`
`of patients with non—pretreated advanced I Iodgkin's disease (stage IIIA, lllB, IVA, IVB)
`
`in a multieentre randoiiiized study.
`
`Treatment regimens
`CVPP (n = 40)*
`
`Cyclophospliamide
`
`Vinblastine
`
`Proearhazitie
`
`Prednisoloue
`
`
`
`600 mg/m'’ i.v. on days I + 8
`
`6 mg/111*‘ i.v. on days 1 + 8
`
`100 mg oral on days 1 — 14
`
`4-0 ing/mi oral on days 1 * I4
`
`DBVB — alternating with the above CVPP regimen (n = 40)”
`
`Dauuorubicin
`
`Blt"0I'l1‘)’ClI'l
`
`Viiieristine
`
`Bendaniustine
`
`
`
`25 mg/mi i.v. on days 1 + T5
`
`10 ing/in-' i.n1. on days I + 15
`
`2 n1gi.v. on days 1 + 15
`
`30 mg/m3 i.v. on days I ~ 5
`
`treatrnent—free interval clay 15 to day 28; prednisolone only in cycles 1 and 4
`*
`** treatment-free interval day 15 to day 28
`
`The results oftliis treatmeiit demonstrate that the two therapeutic regimens are equally
`
`effective. No statistically signiticzint differences were detectable.
`
`Study results
`Number of
`
`patients
`
`
`
`No
`remission
`
`DBVB — alternating with the above CVPP regimen
`
`35<57f=>
`W30)
`
`509-5)
`
`With the aim of reducing the risk oflate complications of combined radioehemotherapy
`
`in patients with non-preI:reated Ilodgkinis disease and ofminimizing risk Factors, Herold
`
`et al. (26; 37) studied the ef'fie:1cy ofreduced r:1dio~ and elielnothei-apy as sandwich theiapy‘.
`
`The following parameters were regarded as particular risks: large mediastinal tumour,
`
`B—svinptoms, extensive abdominal involveznent. extranodal involvement — especially of
`
`the lungs <Lu1favo1.1rable histologie siibtypes ~ espeeiaily lyinphoeyte-depleted histologie
`
`subtypes —, increase in sedimentation rate ofrnore than 50 mm in the first hour.
`
`The therapeutic regimen developed in the pilot study is shown below.
`
`21
`
`FRESENIUS KABI 1007-0020
`
`

`
`Therapeutic regimen
`CVPP!ABVCy hybrid regimen
`
`Cyclopliospliarnide
`
`600 mg/rn" i.v. on day 1
`
`Vinblastine
`
`Procarbazine
`
`Prednisolone
`
`Doxorubicin
`
`Bleornycin
`
`Vincristine
`
`6 lT1g/111'! i.v. on day 1
`
`100 mg/rn*' oral on days 1 —— 7
`
`40n1g/1111 oral on days 1 — 14
`
`E5 mg/In" i.v. on day 8
`
`15 mg/ml i.m. on day 8
`
`2 mg iv. on day 8
`
`Bendainustine
`
`30 mg/In” i.v. on days 8 — 13
`
`Treat1nent—li-ee interval day 15 to day 28; repetition day '29
`
`Radiotherapy was administered with -,1 reduced focal dose of"_’-5 Cy as involved field
`
`irradiation, and chernotherapy comprised six cycles.
`
`[[1 addition to the favourable results in terms ofrelnission rate (81% patients with CR, 13%
`
`with PR and only 7% 11or1—respo11ders) the Ehyear survival data ofthe pilot study are signi-
`fic:1_ut.
`
`After :1 median observation period oF108 1nonths,.'?.7 oI"35 patients are in their first com-
`
`plete remission. Eight patients relapsed (after 14, '30, 30, 31,36, 38, 48 and 77 months).
`
`Renewed complete remission could be achieved in 3 of these 8 patients by salvage therapy.
`
`The proportion of patients classifiable as responders (= rate of Freedom from therapeutic
`
`fililure) was 78% (after 5 years) and 70% (after 9 vea1‘s).Total survival after 5 and 9 years was
`
`83% and 73% respectively.
`
`In a subsequent phase II! study (28), I00 nompretreated patients were treated with either
`
`cyclophosphamide or bendamustine, each combined with vinblastine. procarba?.ine,predni—
`
`solone, doxorubicin, vincristine and bleomycin and also received radiotherapy. The results
`
`of the above pilot study were confirrned. Comparable remission and survival rates were
`
`determined For both therapeutic regimen5.The CR rate was 88% in the hendamustine
`
`group and 81% in the eyclophosphamide group. The 5-year total survival rate at interim
`
`analysis (68 months follow-up) was 83% and 80% respectively (bendamustine and cyclo-
`
`phosphamide group)-
`
`6.2 Non-Hodgkin lymphoma (NHL)
`
`5.2.1 Indolent lymphoma
`Ruflfert et al. (56) studied the efficacy ofhend;nnL1stine in combination with vincristine
`
`and prednisolone (BOP) in 31 patients with refractory,progressive,1naligi1a_nt NI-LL (see
`
`table).
`
`FRESENIUS KABI 1007-0021
`
`

`
`Patient characteristics
`
`Stages
`[11 A / [[1 B
`
`IV A I {V B
`
`1]
`
`20
`
`Histology according to Kiel classification
`
`10
`
`I?
`
`9
`
`9
`23
`
`15
`
`
`
`Low grade
`
`Intermediate grade
`
`High grade
`Previous treatment
`
`Knospe
`COP
`
`CHOP—Bleo
`
`Relapse rate
`
`
`
`
`
`1" relapse
`
`2"‘ relapse
`
`3"‘ relapse
`
`Treatment regimen
`Cl1e1notl1er2tpy was given according to the following regimen (repetition day 32 :
`
`Belldanlustine
`
`Vincristine
`
`Prednisolone
`
`
`
`60 111g/I112 i.v. as a short infizsion over 1 hour on days 1 r 5
`
`or 100 lng/I113 i.v. on days 1 — 3
`
`1.4 mg/m-' i.v. on day 1 (up to l’I1:L‘{. 2 mg)
`
`100 n1g/tn’ i.v. on clays I — 5
`
`The study results conclusively show the eftectiveztetzs of the treatment regimen as a second-
`
`line or tlLirCl—lj.ne therapy in patients with Knospe, COP and CI-IC)P—Bleo refiactory Inelig-
`nzmt NHL.
`
`Study results
`Number of
`patients
`
`
`
`
`
`PD
`I1 (Va)
`
`The patients with complete remission showed a 1-enjission duration of 5 to 34+ 1'l10tltl'lS
`
`(median 12.4 months) and patients with PR showed a remission dumtion of 1 to 1*) months
`
`(ntedian 9.8 1nontl1s).Tl1e total survival rate was 68% for the ohset-vation period. Malignant
`
`NHL was only in 13% of the patients the cause ofeleatll.
`
`23
`
`FRESENIUS KABI 1007-0022
`
`

`
`Evaluation ofthe study results taking into account the nialignaney-grade showed that
`
`rtltliough no complete remissions were acliieved for low—g1-ade Nl IL, all patients achieved
`
`partial 1-etnission.The 1-eniission duration was between 3 and 19 months.
`
`Six and five patients with intermediate or high—grade Nl'II., respectively, achieved complete
`
`re1I1ission.;nid 5 and 2 patients, respectively. achieved partial reniission.The results obtained
`
`in these patient samples are partietilar